In response to NIDA RFA-DA-08-024 Extinction and pharmacotherapies for drug addiction: Cocaine patients show a remarkable persistence of desire and arousal to cocaine cues, months or even years after the last dose of drug. These "extinction-resistant" responses may be due to cocaine patients'documented (structural and functional) deficits in the prefrontal cortex (PFC) - a region necessary for modulating the downstream limbic ("GO!") regions - and for the new learning that underlies extinction. Adding to this anatomical challenge, cocaine patients undergoing laboratory-based extinction remain keenly aware that "real-world" cues are still an excellent predictor of drug availability. This discrimination is not difficult (despite a PFC deficit!), and undermines generalization of laboratory extinction to "real-world" cues. We have recently developed a novel "unseen" cue paradigm that may minimize both "the PFC problem" and " the awareness problem" undermining conventional extinction efforts. This paradigm recently provided the first evidence that cocaine cues (33 msec, backward-masked) can trigger the subcortical limbic reward circuitry (amygdala, striatum/pallidum, insula, OFC) even when presented entirely outside awareness- i.e., "unseen" (PLoS ONE, 2008). Further, repeated, unreinforced presentations of the "unseen" cues did not activate the dorsal PFC, suggesting the PFC may not be as important for extinction outside awareness. Pilot data from this new paradigm suggests DA-modulating medications (e.g., varenicline) will be a clear assist in reducing the limbic activation to cocaine cues, consistent with our recent demonstration of striatal dopamine (DA) as one brain substrate for cue effects (J. Neuroscience, 2006). We will thus use an extinction-variant of the "unseen" cue paradigm and a between-group 2 x 2 ("seen" vs. "unseen") x ( varenicline vs. placebo ) design to address the following aims in cocaine patients (n=22 per group) during a 15-day stay in a controlled residential setting: Specific Aim 1) Will extinction conducted outside awareness, using "unseen" cocaine cues, be more effective than conventional extinction with visible cues (as indexed by reduced limbic activation to the same cues, 1 hour and 1 day later ("savings") and to realistic cocaine videos 48 hours later ("generalization")? Specific Aim 2): Will varenicline (1 mg b.i.d.) facilitate either or both extinction approaches, as compared to placebo? Exploratory Aim: Finally, as our lab has recently demonstrated that the limbic response to drug cues is much stronger in carriers of the "inefficient" variant of the dopamine transporter (DAT 9 VNTR), we will determine the contribution of genetic variations in DA transmission for the response to cocaine cues, to our extinction procedures, and to varenicline. The proposed basic research will have immediate clinical relevance, as varenicline is already FDA- approved for human use (for cigarette smoking) and - if effective -- could readily be combined with inexpensive "off-magnet" extinction paradigms for the treatment of cocaine addiction. PUBLIC HEALTH RELEVANCE: Varenicline-assisted extinction of the limbic response to "seen" and "unseen" cocaine cues. The current project tests whether extinction of the brain response to cocaine cues can occur outside awareness, and whether extinction can be facilitated by the partial agonist varenicline.